Loss of RSPO3 as a potential mechanism of greater invasiveness in prostate cancer.
Bibliographic record
Abstract
333 Background: While prostate cancer can often manifest as an indolent disease, locally-advanced or metastatic disease can cause significant morbidity or mortality. Better understanding of molecular mechanisms leading to more aggressive presentations can lead to identification of prognostic or predictive biomarkers, as well as to possible therapeutic targets. Methods: We describe the generation of prostate cancer cell lines that have been selected through a course of hypofractionated radiotherapy. We show that R-spondin 3, a protein implicated previously as a marker of aggressive disease in colorectal and non-small cell lung cancer, is downregulated in these cell lines compared to parental cells. Then, we test the functional consequences of R-spondin 3 downregulation by siRNA-mediated interference using in vitro assays of radiation resistance, proliferation, and invasiveness . Experiments investigating any change in metastatic propensity following R-spondin 3 downregulation are forthcoming. We further investigate signaling pathways that may be implicated in the mechanism of R-spondin 3 action. Lastly, we use the Oncomine Platform to look for any changes in R-spondin 3 levels between normal prostate tissue and prostate adenocarcinoma. Results: Although siRNA-mediated loss of R-spondin 3 does not confer radiation resistance in vitro, it does result in increased invasiveness in Matrigel assays. Paradoxically, R-spondin 3 downregulation results in decreased proliferation. Interference with R-spondin 3 also results in decreased β-catenin, ERK, and Akt signaling, but increased JNK signaling. In support of our in vitro results, R-spondin 3 expression is lower in human prostate adenocarcinoma compared to normal prostate in several gene expression datasets. Conclusions: Our preliminary data suggest that R-spondin 3 loss may lead to increased disease aggression via altered cell signaling. R-spondin 3 downregulation may represent a potential biomarker to identify patients at greater risk of developing locally advanced or metastatic disease, or a potential mechanism to target in future therapeutic efforts.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".